This invention relates to the discovery that 3,3-Bis(p-hydroxyphenyl)phthalide (phenolphthalein) is an effective treatment for the viral infections Acquired Immunodeficiency Syndrome (AIDS) HTLF-111/LAV and Acquired Immunodeficiency Syndrome (AIDS) Related Complex C) in humans.
Phenolphthalein has long been known as one of a group of primary diphenylmethane cathartics. The cathartic effect of Phenolphthalein was reportedly discovered in 1902 and since that time it has been widely employed in laxative formulas. It is also reported that Phenolphthalein is relatively nontoxic. Goodman & Gillman Pharmacological Basis of Therapeutics (4th Edition 1977) pgs 1021 and 1022. Phenolphthalein is also used as an indicator in the titration of mineral and organic acids and most alkalis
Applicant also disclosed methods and uses of phenolphthalein as an antiviral drug in TREATMENT OF HERPES SIMPLEX INFECTIONS AND ACNE, U.S. Pat. No. 4,256,763, filed Sept. 19, 1978 and issued Mar. 17, 1981; and as an antiviral drug for treating mammalian inflammatory viral infections in U.S. Pat. Department No. 4,588,744 filed Jan. 27, 1981 and issued May 13, 1986.
Acquired Immunodeficiency Syndrome (AIDS) HTLV-111/LAV virus is a sexually transmitted terminal disease that ravages the body's immune system and kills by a variety of infections, cancers and brain disorders. It has hit hardest at homosexuals and intravenous drug abusers in the United States, but it is a heterosexual disease in Africa and increasing numbers of cases of heterosexual transmission are being found in the United States and elsewhere.
The AIDS virus was first discovered in May 1983 by Dr. Luc Montagnier of the Pasteur Institute in Paris, France, and by Dr. Robert Gallo of the National Cancer Institute in Bethesda, Md. the following Spring, when he produced the virus in large quantities.
Much evidence suggests that whenever viral infection leads to chronic disease, some sort of breakdown or weakness of the immune system plays a contributing role. The AIDS virus directly attacks helper T cells, or T Lymphocytes as they are known, invading and preventing them from functioning as the initiator of all the immune system response of the human body. With the T cells unable to perform their infection fighting role the AIDS viruses replicate and reproduce themselves a thousand times as fast as any other type virus, spreading with devastating speed to other T cells, destroying them in turn and the immune system of the human body until the patient is beyond recovery. Opportunistic infections attack people when their immune systems are weakened, such as Pneumocystis Carinii pneumonia, a lung infection, Karposi's Sarcoma, a cancer, Candida Albicans, a fungis, Herpes Simplex types 1 & 2, a virus infection, Herpes Zoster, Cytomegalo-Virus and Epstein-Barr viruses.
There are many people infected with the AIDS virus that do not develop the deadly syndrome. They have persistent infections and suffer a mild version of immune-system depression with symptoms that include malaise, weight loss, fevers and swollen lymph nodes. This is the syndrome designated Acquired Immunodeficiency Syndrome (AIDS)-Related Complex or ARC. Much of the time this syndrome developes into full blown AIDS.
Sample studies based on blood tests suggest that millions of Americans are symptomless carriers of the virus. Authorities speculate that 10% of these people without symptoms but with antibodies to the virus, meaning they have been exposed, will develop AIDS within five years.
Progress in the treatment of AIDS has been slow. Some potential antiviral substances have been tested and while they stop or slow replication of the AIDS virus temporarily they Produce debilitating side effects, are not effective cures, and no such cure is in sight. Among these drugs are HPA-23 developed by the Pasteur Institute, and Foscarnet developed in Sweden, Suramin originally used to treat sleeping sickness, Dideoxycytidine, and the first U.S. approved drug for use 3'-Azido-3'-Deoxythymidine "AZT" that while limitedly effective has reportedly caused damage to the marrow of some patient's bones and could have even worse long range effects.
It is an object of the present invention to provide a fast acting, effective treatment of the inflammatory viral infection Acquired Immunodeficiency Syndrome (AIDS) HTLV-111/LAV and Acquired Immunodeficiency Syndrome (AIDS)-Related Complex ARC.
It is a further object of this invention to Provide a fast acting effective treatment that will suppress the AIDS virus HTLV-111/LAV and at the same time rejuvenate, rebuild, and reconstitute the immune system response.
It is a further object of this invention to provide a fast acting, effective treatment of opportunistic infections that attack persons when their immune systems are weakened by AIDS and RC infections such as Pneumocystis Carinii pneumonia, a 1 lung infection, Karposi's Sarcoma, a cancer, Candida Albicans a fungis, Herpes Zoster, HerPes Simplex types 1 and 2, Cytomegalo-virus, and Epstein-Barr virus.
The daily maintenance dose for laxative effect of Phenolphthalein and the management thereof is 50 to 100 milligrams in twenty-four hours. Therefore dosage of 200 milligrams or more of phenolphthalein every twelve hours would be prohibitive unless the laxative effect of the drug was suppressed and inhibited. Yellow phenolphthalein commonly used in most laxative products is two to three times stronger as a laxative-cathartic than the pure white Phenolphthalein U.S.P./N.F. and the harsh cathartic effect of the yellow phenolphthalein is difficult to suppress, if possible at all.
It has been discovered by the inventor that the laxative effect of Phenolphthalein can be almost totally suppressed, and practically eliminated by combination with a Prostaglandins Synthetase inhibitor which may be administered one hour before the dosage of the phenolphthalein is given, or contemporaneously therewith, or combined in a composition with phenolphthalein. This would allow the use of high dosages of Phenolphthalein where indicated to effectively use the antiviral Prostaglandin Biosynthesis stimulating properties of the drug.
It would thus be desirable to provide a pharmaceutical composition that suppresses the laxative effect of phenolphthalein at high dosage levels but does not reduce its antiviral Prostaglandin Biosynthesis stimulating activity or enhancement of immunological response.
Indomethacin and Aspirin were found to be two Prostaglandins Synthetase Inhibitors that could be effectively used with Phenolphthalein to accomplish this purpose.
Accordingly it is an object of the present invention to provide novel pharmaceutical compositions containing phenolphthalein and a prostaglandins synthetase inhibitor.
It is also an obJect of the present invention to provide a method and composition of matter for treating the Acquired Immunodeficiency Syndrome (AIDS) and Acquired Immunodeficiency Syndrome (AIDS) Related Complex (ARC) infections by oral administration of the aforesaid pharmaceutical compositions.
Phenolphthalein is a potent stimulant of Prostaglandin Biosynthesis. Prostaglandins function primarily as agents of bodily defense in response to injurious stimulus. Prostaglandins a naturally occurring group of substances represent a diverse family of oxygenated derivatives formed from certain polyunsaturated fatty acids. The biosynthesis of Prostaglandins consists of many steps that involve a variety of different enzymes and cofactors.
It is well established that Prostaglandins are important immunoregulators and their role in immune response is currently being investigated. The stimulation of Prostaglandin Biosynthesis by Phenolphthalein will greatly increase the issue of metabolites to act as local immunoregulators at all physiological and pathological situations in the body. Proliferation of Lymphocyte T Helper cells can be induced by Prostaglandins.
Immune responses are complex often requiring cooperation between several cell types, genetic and other immune-controlling influences, operating at a number of levels, providing an extremely complex regulatory system that is only beginning to be understood.
Prostaglandins are not normally stored in the tissues but are biosynthesized from fatty acids as and when required on injurious stimulus. Prostaglandins are involved in many physiological and pathological situations. They are involved in the protection of renal function against excessive activity of the pressor hormones, remaining dormant until challanged. The lungs are involved in the metabolism of Prostaglandins but little is known about the biological activity of the metabolites that are formed. Prostaglandins have potent effects upon Bronchial and Pulmonary vascular smooth muscle and the lungs have evolved enzyme systems in response to their biological activity.
Prostaglandins are metabolized by tissues to a variety of products in enzymatic reactions, everywhere in the body resulting from injurious stimulus. They are synthesized and released from various regions of the body, including for example the Central Nervous System, the Cerebro Spinal Fluid, Coronary Arteries, all layers of the Heart, the Spleen, the Brain, the Kidneys, the Liver and the Semen, a total body defense system activated instantly on localized pathogenic stimulus. But like Human Interferon the Prostaglandins at their normal synthesized levels of concentration are not strong enough to inhibit the growth of the invading pathogens. What is needed is an excitant to stimulate the rate of Prostaglandin Biosynthesis to levels many times higher than that now occurring naturally. It is believed that Phenolphthalein will provide that needed stimulant. Prostaglandin Biosynthesis stimulated by the oral administration of effective doses of Phenolphthalein will cause metabolic formulations, in powerful concentrations at high levels of Prostaglandins effective against among other infections, the Acquired Immunodeficiency Syndrome (AIDS)HTLV-111/LAV and Acquired Immunodeficiency Syndrome (AIDS) Related Complex (ARC).
It was found that while the Phenolphthalein laxative effect stimulated by Prostaglandin Biosynthesis activity will be suppressed by ingestion of Aspirin or Indomethacin, Prostaglandin Synthetase inhibitors, for a limited dose related time, the response of the Prostaglandins in all other areas of the body as immunoregulators is not diminished.
It is an object of the present invention to provide a method and composition of matter for treating the Acquired Immunodeficiency Syndrome (AIDS) HTLV.TM.111/LAV and Acquired Immunodeficiency Syndrome (AIDS) Related Complex infections by oral administration of Phenolphthalein in effective doses to stimulate and increase the rate of Prostaglandin Synthesis to levels many times higher than that now occurring naturally and thereby enhance and reconstitute the immune system and increase the numbers of Helper-Inducer T Lymphocytes in combatting the infections.